Based on this situation it was an object of the present invention to provide means for a more versatile temperature controlled manipulation of a sample in a microelectronic device.
This objective is achieved by a microelectronic device and use according to representative embodiments described herein.
The microelectronic device according to the present invention is intended for the manipulation of a sample, particularly a liquid or gaseous chemical substance like a biological body fluid which may contain particles. The term “manipulation” shall denote any interaction with said sample, for example measuring characteristic quantities of the sample, investigating its properties, processing it mechanically or chemically or the like. The microelectronic device comprises the following components:    a) A sample chamber in which the sample to be manipulated can be provided. The sample chamber is typically an empty cavity or a cavity filled with some substance like a gel that may absorb a sample substance; it may be an open cavity, a closed cavity, or a cavity connected to other cavities by fluid connection channels.    b) A “heating array” that comprises a plurality of local driving units and (spatially and functionally) associated heating elements, wherein said heating elements can exchange heat with at least a sub-region of the sample chamber when being driven with electrical energy by the associated local driving unit. The heating elements may preferably convert electrical energy into heat that is transported into the sample chamber. It is however also possible that the heating elements absorb heat from the sample chamber and transfer it to somewhere else under consumption of electrical energy. The local driving units are located more or less near the heating elements and coupled to them.
In the most general sense, the term “array” shall in the context of the present invention denote an arbitrary three-dimensional arrangement of a plurality of elements (e.g. the heating elements and the local driving units). Typically such an array is two-dimensional and preferably also planar, and the elements are arranged in a regular pattern, for example a grid or matrix pattern.
Furthermore, it should be noted that a “heat exchange with a sub-region of the sample chamber” is assumed if such an exchange is strong enough in the sub-region to provoke desired/observable reactions of the sample. This definition shall exclude small “parasitic” thermal effects that are inevitably associated with any active process, e.g. with electrical currents. Typically, a heat flow in the sense of the present invention is larger than 0.01 W/cm2 and will have a duration in excess of 1 millisecond.    c) A control unit for selectively controlling the local driving units, i.e. for determining the supply of electrical energy to the heating elements.    d) Means for compensating variations of the individual characteristics of the local driving units (CU2), wherein said means may particularly be realized within the local driving units and/or the control unit.
The aforementioned microelectronic device has the advantage that the temperature profile in the sample chamber can be very precisely adjusted with the help of the heating array, wherein the control of the individual heating elements is achieved via local driving units. Such local driving units can take over certain control tasks and thus relieve the control unit and in addition can increase the efficiency of the array by avoiding leakage of driving currents between e.g. an external current source and an array of heating elements.
Moreover, the device addresses the problem that even with an identical design of driving units, the components and circuitry from which they are constructed have statistical variations in their characteristics which lead to variations in the behavior of the driving units. Addressing different driving units with the same voltage may then for example lead to different results, e.g. different current outputs to the heating elements. This makes a precise control of temperature in the sample chamber difficult if not impossible. The microelectronic device therefore incorporates means for compensating variations in the individual characteristic values of the driving units. This allows a control with much higher accuracy and allows to do without feedback control procedures.
The means for compensating variations of the individual characteristics of the local driving units may particularly comprise hardware components (capacitors, transistors etc.) for adjusting their individual characteristics.
In another embodiment, the control unit is adapted to drive the local driving units in an operating range where variations of their individual characteristics have negligible influence on the produced heat exchange. Particular examples of this and the aforementioned embodiment are disclosed in the Figures.
In a further development of the invention, the local driving units are coupled to a common power supply line, and the heating elements are coupled to another common power supply line (e.g. ground). In this case each local driving unit determines the amount of electrical energy or power that is taken from the common power supply lines. This simplifies the design insofar as properly allocated amounts of electrical energy do not have to be transported through the whole array to a certain heating element.
In another embodiment of the microelectronic device, at least a part of the control unit is located outside the array of heating elements and local driving units and connected via control lines for carrying control signals to the local driving units. In this case the outside part of the control unit can determine how much electrical energy or power a certain heating element shall receive; this energy/power needs however not be transferred directly from the outside control unit to the heating element. Instead, only the associated information has to be transferred via the control signals to the local driving units, which may then extract the needed energy/power e.g. from common power supply lines.
In a preferred realization of the aforementioned embodiment, the control signals are pulse-width modulated (PWM). With such PWM signals, the local driving units can be switched off and on with selectable rate and duty cycle, wherein these parameters determine the average power extraction from common power supply lines. The individual characteristics of the local driving units are then less critical as only an on/off behavior is required. It is also possible to drive the heaters or field electrodes with pulse amplitude modulation (PAM), pulse frequency modulation (PFM) or a combination of modulation techniques.
In a further development of the aforementioned embodiments, the local driving units comprise a memory for storing information of control signals transmitted by the outside part of the control unit. Such a memory may for example be realized by a capacitor that stores the voltage of the control signals. The memory allows to continue a commanded operation of a heating element while the associated control line is disconnected again from the driving unit and used to control other driving units.
In a typical design of the microelectronic device, at least one local driving unit comprises a transistor which produces for a given input voltage V at its gate an output current I (which will be fed to the heating element) according to the formulaI=m·(V−Vthres)2,wherein m and Vthres are the individual characteristic values of the transistor. The formula illustrates that local driving units with different values of m and Vthres will behave differently when controlled with the same voltage.
In the aforementioned case, the at least one local driving unit preferably comprises circuitry to compensate for variations in Vthres and/or circuitry to compensate for variations in m.
The driving units preferably each comprise a memory element, e.g. a capacitor, coupled to the control gate of said transistor and circuitry to charge this memory element to a voltage that compensates Vthres or that drives the transistor to produce a predetermined current I. Thus the application of e.g. a simple capacitor may suffice to compensate individual variations in the very important case of driving units based on a transistor of the kind described above. In the case where variations in both m and Vthres are to be compensated, the circuitry may especially comprise a current mirror circuit or a single transistor current mirror. Further details with respect to an associated circuitry will be described in connection with the Figures.
The microelectronic device may optionally comprise at least one sensor element, preferably an optical, magnetic or electrical sensor element for sensing properties of a sample in the sample chamber, for example the concentration of particular target molecules in a fluid. A microelectronic device with magnetic sensor elements is for example described in the WO 2005/010543 A1 and WO 2005/010542 A2. Said device is used as a microfluidic biosensor for the detection of biological molecules labeled with magnetic beads. It is provided with an array of sensor units comprising wires for the generation of a magnetic field and Giant Magneto Resistance devices (GMRs) for the detection of stray fields generated by magnetized beads.
If a plurality of the aforementioned sensor elements is present, these elements are preferably arranged in a “sensing” array.
According to a further development of the aforementioned embodiment, the heating elements of the heating array and the sensor elements of the sensing array are aligned with respect to each other. This “alignment” of heating and sensor elements means that there is a fixed (translation-invariant) relation between the positions of the heating elements in the heating array and the sensor elements in the sensing array; the heating and sensor elements may for example be arranged in pairs, or each heating element may be associated with a group of several sensor elements. Due to an alignment, the heating and sensor elements interact similarly at different locations. Thus uniform/periodic conditions are provided across the arrays. A preferred kind of alignment between the sensor and the heating elements is achieved if the patterns of their arrangement in the sensing array and the heating array, respectively, are identical. In this case, each sensor element is associated with just one heating element.
In an alternative embodiment, more than one heating element is associated to each sensor element. This allows to create a spatially non-uniform heating profile, which can result in either a spatially non-uniform or a spatially uniform temperature profile in the region of one sensor element and thus an even better temperature control. Preferably, there is additionally an alignment of the above mentioned kind between heating elements and sensor elements.
In another embodiment of a microelectronic device with a heating array and a sensing array, said arrays are disposed on opposite sides of the sample chamber. Such an arrangement can readily be combined with known designs of biosensors as only the cover of the sample chamber has to be replaced by the heating array.
In an alternative embodiment, the heating array and the sensing array are disposed on the same side of the sample chamber. In this case, the arrays may be arranged in a layered structure one upon the other, or they may be merged in one layer.
In the aforementioned embodiment with a layered structure, the sensing array is preferably disposed between the sample chamber and the heating array. Thus it will be as close as possible to the sample chamber which guarantees an optimal access to the sample.
The heating elements may particularly comprise a resistive strip, a transparent electrode, a Peltier element, a radio frequency heating electrode, or a radiative heating (IR) element. All these elements can convert electrical energy into heat, wherein the Peltier element can additionally absorb heat and thus provide a cooling function.
The microelectronic device may optionally comprise a cooling unit, e.g. a Peltier element or a cooled mass, in thermal contact with the heating array and/or with the sample chamber. This allows to reduce the temperature of the sample chamber if necessary. In combination with a heating array for the generation of heat, a cooling unit therefore enables a complete control of temperature in both directions.
While the heating elements are in most practical cases (only) capable of generating heat, at least one of them may optionally also be adapted to remove heat from the sample chamber. Such a removal may for example be achieved by Peltier elements or by coupling the heating elements to a heat sink (e.g. a mass cooled with a fan).
The microelectronic device may optionally comprise at least one temperature sensor which makes it possible to monitor the temperature in the sample chamber. The temperature sensor(s) may preferably be integrated into the heating array. In a particular embodiment, at least one of the heating elements is designed such that it can be operated as a temperature sensor, which allows to measure temperature without additional hardware.
In cases in which a temperature sensor is available, the control unit may be coupled to said temperature sensor and adapted to control the heating elements in a closed loop according to a predetermined (temporal and/or spatial) temperature profile in the sample chamber. Though the microelectronic device achieves already a very precise (feedforward) temperature control due to the means for compensating circuitry variations, a feedback may further improve accuracy and allow to provide optimal conditions for the manipulation of e.g. a sensitive biological sample.
The microelectronic device may further comprise a micromechanical or an electrical device, for example a pump or a valve, for controlling the flow of a fluid and/or the movement of particles in the sample chamber. Controlling the flow of a sample or of particles is a very important capability for a versatile manipulation of samples in a microfluidic device.
In a particular embodiment, at least one of the heating elements may be adapted to create flow in a fluid in the sample chamber by a thermo-capillary effect. Thus its heating capability can be exploited for moving the sample.
If it is necessary or desired to have sub-regions of different temperature in the sample chamber, this may optionally be achieved by dividing the sample chamber with a heat insulation into at least two compartments. Particular embodiments of this approach will be described in more detail in connection with the Figures.
An electrically isolating layer and/or a biocompatible layer may be disposed between the sample chamber and the heating and/or a sensing array of sensor elements. Such a layer may for example consist of silicon dioxide SiO2 or the photoresist SU8.
In a further embodiment of the invention, the control unit is adapted to drive the heating elements with an alternating current of selectable intensity and/or frequency. The electrical fields associated with such an operation of the heating elements may in certain cases, for example in cases of di-electrophoresis, generate a motion in the sample if they have an appropriate intensity and frequency. On the other hand, the intensity and frequency of the alternating current determines the average rate of heat production. Thus it is possible to execute a heating and a manipulation function with such a heating element simply by changing the intensity and/or frequency of the applied current appropriately.
The heating element(s) and/or field electrode(s) may preferably be realized in thin film electronics.
When realizing a microelectronic device according to the present invention, a large area electronics (LAE) matrix approach, preferably an active matrix approach may be used in order to contact the heating elements and/or sensor elements. The technique of LAE, and specifically active matrix technology using for example thin film transistors (TFTs) is applied for example in the production of flat panel displays such as LCDs, OLED and electrophoretic displays.
In the aforementioned embodiment, a line-at-a-time addressing approach may be used to address the heating elements by the control unit.
According to a further development of the microelectronic device, the interface between the sample chamber and the heating and/or a sensing array is chemically coated in a pattern that corresponds to the patterns of the heating elements and/or sensor elements, respectively. Thus the effect of these elements can be combined with chemical effects, for example with the immobilization of target molecules out of a sample solution at binding molecules which are attached to the interface.
The invention further relates to the use of the microelectronic devices described above for molecular diagnostics, biological sample analysis, chemical sample analysis, food analysis, and/or forensic analysis. Molecular diagnostics may for example be accomplished with the help of magnetic beads that are directly or indirectly attached to target molecules.
A programmable heating array as it was described in numerous embodiments above can be an extremely important component of a range of devices aimed at medical and health and wellness products. A main application is to use a heating array in a biochip, such as underneath a biosensor or underneath reaction chambers, where controlled heating provides functional capabilities, such as mixing, thermal denaturation of proteins and nucleic acids, enhanced diffusion rates, modification of surface binding coefficients, etc. A specific application is DNA amplification using PCR that requires reproducible and accurate multiplexed (i.e. parallel and independent) temperature control of the array elements. Other applications could be for actuating MEMS related devices for pressure actuation, thermally driven fluid pumping etc.
Like reference numbers/characters in the Figures refer to identical or similar components.